During erythropoiesis, erythropoietin stimulates induction of erythroid transcription factors that activate expression of erythroid genes including the erythropoietin receptor that results in increased sensitivity to erythropoietin. DNA binding of the basic-helix-loop-helix transcription factor, TAL1/SCL is required for normal erythropoiesis. A link between elevated TAL1 and excessive erythrocytosis is suggested by erythroid progenitor cells from a patient that exhibits unusually high sensitivity to erythropoietin with concomitantly elevated TAL1 and erythropoietin receptor expression. We found that TAL1 regulates erythropoietin receptor expression mediated via three conserved E-box binding motifs (CAGCTG) in the erythropoietin receptor 5 untranslated transcribed region. TAL1 increases association of the GATA-1/TAL1/LMO2/Ldb1 transcription activation complex to the region that includes the transcription start site and the 5 GATA and 3 E-box motifs flanking the erythropoietin receptor transcription start site suggesting that TAL1 promotes accessibility of this region. Nucleosome shifting has been demonstrated to facilitate TAL1 but not GATA-1 binding to regulate target gene expression. Accordingly, we observed that with induced expression of erythropoietin receptor in hemotopoietic progenitor cells, nucleosome phasing shifts to increase the linker region containing the erythropoietin receptor transcription start site and TAL1 binds to the flanking 5 GATA and 3 E-box regions of the promoter. These data suggest that TAL1 binds to the erythropoietin receptor promoter to activate erythropoietin receptor expression and provides a potential link to elevated erythropoietin receptor expression leading to hypersensitivity to erythropoietin and the resultant excessive erythrocytosis. Interestingly, forced increase of erythropoietin receptor in differentiating erythroid progenitor cells does not increase fetal hemoglobin.